Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes

Fan Zhang, Anna Helena Jonsson, Aparna Nathan, Nghia Millard, Michelle Curtis, Qian Xiao, Maria Gutierrez-Arcelus, William Apruzzese, Gerald F M Watts, Dana Weisenfeld, Saba Nayar, Javier Rangel-Moreno, Nida Meednu, Kathryne E Marks, Ian Mantel, Joyce B Kang, Laurie Rumker, Joseph Mears, Kamil Slowikowski, Kathryn Weinand, Dana E Orange, Laura Geraldino-Pardilla, Kevin D Deane, Darren Tabechian, Arnoldas Ceponis, Gary S Firestein, Mark Maybury, Ilfita Sahbudin, Ami Ben-Artzi, Arthur M Mandelin 2nd, Alessandra Nerviani, Myles J Lewis, Felice Rivellese, Costantino Pitzalis, Laura B Hughes, Diane Horowitz, Edward DiCarlo, Ellen M Gravallese, Brendan F Boyce; Accelerating Medicines Partnership: RA/SLE Network; Larry W Moreland, Susan M Goodman, Harris Perlman, V Michael Holers, Katherine P Liao, Andrew Filer, Vivian P Bykerk, Kevin Wei, Deepak A Rao, Laura T Donlin, Jennifer H Anolik, Michael B Brenner, Soumya Raychaudhuri.
Nature. 2023-11-08;623(7987):616-624.
Abstract
Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.

Related data

Data summary
CITE-seq single-cell expression matrices and sequencing and bulk expression matrices are available on Synapse.
Data summary
Associated genotype and clinical data are available through the Arthritis and Autoimmune and Related Diseases Knowledge Portal (ARK Portal).
Data summary
A cell browser website is available to visualize our data and results.
Data summary
AMP Phase 1 single-cell data from ref. 8 are available on Immport (SDY998). PEAC clinical trial RNA-seq data from ref. 6 are available on ArrayExpress (E-MTAB-6141). R4RA clinical trial RNA-seq data from ref. 44 are available on ArrayExpress (E-MTAB-11611). Single-cell and bulk RNA-seq data were aligned to GRCh38 (Ensembl 93), available as part of Cell Ranger v. 3.1.0.
Data summary
The source code for the analyses is available at GitHub
Data summary
The source code for the analyses is available at zenodo